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RNF168-mediated localization of BARD1 recruits the BRCA1-PALB2 complex to DNA damage
Nat Commun. 2021 Aug 18;12(1) :5016
PMID: 34408138 PMCID: PMC8373961 URL: https://www.ncbi.nlm.nih.gov/pubmed/34408138
AbstractDNA damage prompts a diverse range of alterations to the chromatin landscape. The RNF168 E3 ubiquitin ligase catalyzes the mono-ubiquitination of histone H2A at lysine (K)13/15 (mUb-H2A), forming a binding module for DNA repair proteins. BRCA1 promotes homologous recombination (HR), in part, through its interaction with PALB2, and the formation of a larger BRCA1-PALB2-BRCA2-RAD51 (BRCA1-P) complex. The mechanism by which BRCA1-P is recruited to chromatin surrounding DNA breaks is unclear. In this study, we reveal that an RNF168-governed signaling pathway is responsible for localizing the BRCA1-P complex to DNA damage. Using mice harboring a Brca1(CC) (coiled coil) mutation that blocks the Brca1-Palb2 interaction, we uncovered an epistatic relationship between Rnf168(-) and Brca1(CC) alleles, which disrupted development, and reduced the efficiency of Palb2-Rad51 localization. Mechanistically, we show that RNF168-generated mUb-H2A recruits BARD1 through a BRCT domain ubiquitin-dependent recruitment motif (BUDR). Subsequently, BARD1-BRCA1 accumulate PALB2-RAD51 at DNA breaks via the CC domain-mediated BRCA1-PALB2 interaction. Together, these findings establish a series of molecular interactions that connect the DNA damage signaling and HR repair machinery.
Notes2041-1723 Krais, John J Orcid: 0000-0002-3916-3435 Wang, Yifan Patel, Pooja Basu, Jayati Bernhardy, Andrea J Johnson, Neil Orcid: 0000-0002-0276-0009 R01 CA214799/CA/NCI NIH HHS/United States R01 HL150190/HL/NHLBI NIH HHS/United States R01 GM135293/GM/NIGMS NIH HHS/United States T32 CA009035/CA/NCI NIH HHS/United States Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Nat Commun. 2021 Aug 18;12(1):5016. doi: 10.1038/s41467-021-25346-4.